medwireNews: Patients at high risk for severe neurotoxicity after CD19-targeted chimeric antigen receptor–modified T (CAR-T) cell infusion can be identified using a predictive algorithm, indicates a report.

Although CD19 CAR-T cell therapy can be a highly effective treatment for patients with refractory B-cell malignancies, most patients develop cytokine release syndrome (CRS) and some subsequently experience neurotoxicity.

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“An alternative approach to the management of neurotoxicity is to prospectively identify and either exclude or preemptively treat those at highest risk,” explain Cameron Turtle (Fred Hutchinson Cancer Research Center, Seattle, Washington) and colleagues.

Within 28 days of infusion, 53 (40%) patients had experienced at least one grade 1 or worse neurologic adverse event, with 48 (91%) of these patients also having CRS. Seven (5%) of the 133 patients developed grade 4 or worse neurotoxicity and four (3%) patients died as a result.

Multivariable analysis found the risk for neurotoxicity was significantly associated with pre-existing neurologic comorbidities and factors associated with increased CAR-T cell numbers, including cyclophosphamide and fludarabine lymphodepletion, a higher infused CAR-T cell dose, and a higher burden of malignant CD19+ B cells in the marrow. Furthermore, severe toxicity was more common in patients with severe CRS and was associated with systemic vascular dysfunction.

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The researchers developed a classification tree model that indicated patients were at high risk for subsequent grade 4 or worse neurotoxicity if they had a fever at or above 38.9°C, serum IL-6 levels at or above 16 pg/mL, and monocyte chemoattractant protein 1 (MCP1) levels of 1343.5 pg/mL or higher in the first 36 hours after CAR-T cell infusion. The algorithm predicted those at increased risk with a sensitivity of 100% and specificity of 94%.

Of the eight patients who were misclassified as high risk on the basis of these three risk factors, just one (0.75%) did not experience moderate or severe grade 2–3 neurotoxicity and/or grade 2 or worse CRS, “indicating that unnecessary early intervention guided by the classification tree model is rare,” the authors comment.

“Given the potential benefits of CAR-T cell immunotherapy and the almost universally poor outcomes without this approach, exclusion of patients with previous comorbidities does not seem justified,” the team says, suggesting instead that “reduction of the CAR-T cell dose may be appropriate in a subset of high-risk patients.”

Turtle and colleagues write in Cancer Discovery: “Our finding that the serum concentrations of IL6 and MCP1 within 24 hours of CAR-T cell infusion identified patients who subsequently developed severe neurotoxicity provides an opportunity to monitor concentrations of these cytokines to identify those at highest risk.”

Further studies are now required to determine whether preemptive therapy can prevent severe neurotoxicity in such high-risk patients, they conclude.